Dysfunction of the B lymphocyte, an important component of adaptive immunity, is thought to be important in the pathogenesis of lupus nephritis (LN). There are several novel strategies emerging including B-cell depletion by the monoclonal antibodies to B-cell markers, rituximab. We describe an unusual clinical response of a 22-year-old Hispanic woman with class IV LN with vasculitis while on dialysis to cyclophosphamide (CY) and adjunct rituximab. The patient had a history of class III/V LN and was treated with nine months of CY and maintenance therapy with mycophenolate mofetil (MMF) for three years. While on MMF, the patient deve­loped class IV LN with vasculitis leading to end-stage renal disease (ESRD). While the patient was on peritoneal dialysis, the patient was treated with two doses of rituximab and six doses of intravenous CY. The patient responded to this regimen and recovered kidney function within four months. The kidney function remained stable nine months after discontinuing peritoneal dialysis.

While clinical outcomes for proliferative lupus nephritis (LN) have improved since the 1990s with widespread adoption of the National Ins­titutes of Health treatment strategy using intra­venous cyclophosphamide (CY) and cortico-steroids, [1] up to 25% of patients fail to respond to this treatment. [2] In recent years, many new immunosuppressive therapies have been evaluated for LN and many more are under con­sideration. Rituximab is a chimeric monoclonal antibody that specifically binds to the CD20 molecule on the surface of pre- and mature B-cells. It results in profound depletion of the B-cell subsets through induction of cell lysis that may be mediated by complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, or apoptosis. In a pilot open study of five patients with refractory systemic lupus erythematous (SLE), three of whom had neph­ritis, a combination of rituximab and CY with high-dose corticosteroid was well tolerated and resulted in improvement of renal para­meters in two patients. [3]

Case Report

A 22-year-old Hispanic woman presented to the emergency room with a 3-day history of shortness of breath, swelling of the legs, and headache. The patient had a history of class III/V LN with interstitial fibrosis and tubular atrophy diagnosed by biopsy two months prior to presentation. She complained of sudden onset of edema in her legs and shortness of breath upon exertion. The patient denied double vision, dizziness, nausea, vomiting, chest pain, or orthopnea. The patient had no history of smoking, drug or alcohol abuse. Family his­tory was significant for a brother with type 1 Diabetes. Physical examination showed bila­teral pitting edema. The chest, heart, and abdo­minal examinations were unremarkable.

Initially, the patient received three days i.v. methylprednisone, and was initiated on a six month course of i.v. CY. Rituximab was added as an adjunct therapy, at 350 mg/m [2] for two doses two weeks apart. During the first two weeks of therapy, the patient's kidney function deteriorated and creatinine peaked at 6.0 mg/ dL prior to initiation of dialysis. The patient was continued on hemodialysis and then trans­ferred to peritoneal dialysis. At this point it was decided to continue with aggressive the­rapy of CY and steroids in the outpatient set­ting. The patient was followed in clinic once per month. Her creatinine improved from 6.0 mg/dL to 1.1 mg/dL within four months [Table 1]. She was taken off of peritoneal dialysis after 16 weeks of follow-up due to improvement in kidney function. Her renal function remained stable at a creatinine of 1.1 mg/dL one year after the initial insult, and was maintained on MMF and steroids.

The prevalence of clinical renal involvement is between 30% and 90% of SLE patients, with LN being more common in certain ethnic groups and in children, and vasculitis is one of the poorest prognostic factors in any patient. [4]

In LN, usually patients present with worse­ning kidney function, hypertension, edema, and nephritic/nephrotic syndrome. Patients with LN usually also display characteristics of systemic SLE including skin manifestations, synovitis, and serositis. Upon presentation, our patient had hypertension, worsening kidney function, edema and nephritic range proteinuria with hypoalbuminemia.

The etiology of autoimmunity in SLE may be due to loss of self-tolerance as a result of incomplete silencing or deletion of autoreac-tive lymphocytes. [5] Another possible mecha­nism for autoimmunity is dysfunctional apop-tosis characterized by incomplete removal of nuclear remnants, which leads to increased exposure to the immune system and subse­quent recognition. [6] In addition, there are cer­tain genetic linkages in SLE that predispose individuals to renal disease and influence the severity of glomerular disease. [7]

B cells have a central role in the genesis of SLE, as shown by the presence of pathogenic autoantibodies such as anti-double stranded DNA. However, the influence of B cells on SLE is not limited to production of pathogenic autoantibodies. A model of LN in mice showed that a decreased number of B cells prevented the development of SLE, but animals with normal B cell count that were not able to produce antibodies still had occurrence of SLE and LN. [8]

The damage to the kidney in SLE is due to either direct antibody-induced cytotoxicity, immune complex lodging in the glomeruli, or in situ immune complex formation. [9],[10],[11] The three criteria for clinical lupus nephritis are 30% decrease in creatinine clearance, protei-nuria greater than 1000 mg/day, and renal biopsy consistent with active lupus nephrititis. The staging of LN was revised by the Inter­national Society of Nephrology/Renal Pathology Society in 2003, and is shown in [Table 2]. [12]

Several novel treatments for LN involve the strategy of inhibiting B cell activity, other than rituximab, such as LJP-394 (Abetimus so-dium), [13],[14] which was shown in a retrospective observation to improve renal function as it reduced proteinuria. [15] Another anti-B cell drug, Belimumab (LymphoStat-B), [16] showed im­proved disease activity and quality of life scores in patients with moderate disease, [17] and is currently in phase III trials for treatment of SLE. [18] The use of the renal biopsy enables more patient-directed therapy based on histo-logic examination. [19]

Our case supports the aggressive treatment of LN with vasculitis, even if renal replacement therapy is initiated. We aggressively treated our patient to salvage any remaining kidney function. Fortunately, our patient showed im­pressive recovery of kidney function to a creatinine near her baseline. Rituximab may be a beneficial adjunct therapy in class IV LN with vasculitis even though recent trials have been negative for rituximab role in therapy for lupus nephritis with vasculopathy but without vasculitis. Further studies are required to verify the use of aggressive pharmacologic therapy in patients who are dialysis dependent secondary to LN with vasculitis.